Material and methods for treating developmental disorders including comorbid and idiopathic autism

ABSTRACT

The present invention is directed to a method of treating a subject with autism spectrum disorder by administering an acetylaminopropane sulfonate. The acetylaminopropane sulfonate may have the following formula

CROSS-REFERENCE TO RELATED APPLICATION

This application is a National Stage filing of International ApplicationSerial No. PCT/US2010/024008, entitled “Materials and Methods forTreating Developmental Disorders Comorbid and Idiopathic Autism filedFeb. 12, 2010, which claims the benefit under 35 U.S.C. §119 of U.S.Provisional Application No. 61/151,858, filed Feb. 12, 2009, thedisclosures of which are expressly incorporated herein by reference.

FIELD OF THE INVENTION

Various aspects related to drug therapy for the treatment of individualswith developmental disorders, such as autism and the genetic disorderFragile X Syndrome.

BACKGROUND

Autism Spectrum Disorders (ASDs) are defined by the National HumanGenome Research Institute as a broad group of developmental disorderscharacterized by impaired social interactions, problems with verbal andnonverbal communication and respective behaviors or severely limitedactivates and interests. Various forms of autism are included in theDiagnostic and Statistical manual of Mental Disorders DSM-IV-TRcurrently in its forth revised edition and listed as two of five knowncategories of pervasive developmental disorder. ASDs range from a severeform of the disorder called autistic disorder (or classic autism) to amilder form called Asperger's Disorder. A patient presenting symptoms ofeither of these disorders, but not meeting the specific criteria foreither form, may be said to have pervasive developmental disorder nototherwise specified (PDD-NOS).

According to the National Institute for Mental Health an actualdiagnosis of autism requires a thorough clinical examination by aphysician trained in this area of medicine or even a team of health careprofessionals. An individual diagnosis is based on observing anindividual patient's behaviors and measuring the patient's behaviorusing such screening tools such as Autism Diagnosis Interview-Revised(ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Comorbidautism such as autism co-diagnosed with conditions such as Down Syndromeor Fragile X Syndrome (FXS) comprise about 15 percent of all forms ofautism, the remaining 85 percent of cases is of unknown origin andclassified as idiopathic autism.

Given the profound effects that the most severe forms of autism spectrumdisorders, including comorbid and idiopathic forms of the disorder, haveon people afflicted with these disorders and the lack of effectivetreatment options available for these people there is pressing need formaterials and methods to treat these patients, various aspects andembodiments presented herein seek to address this need.

SUMMARY

The invention generally relates to methods of treating fragile Xsyndrome and autism.

In an embodiment, the invention is a method of treating a subject havingan autism spectrum disorder, comprising the step of administering to thesubject a composition that includes at least one homotaurine analog.

In another embodiment, the invention is a method of treating a subjecthaving fragile X syndrome, comprising the step of administering to thesubject a composition that includes at least one homotaurine analog.

In a further embodiment, the invention is a method of treating a humanhaving fragile X syndrome, comprising the step of administering to thehuman a composition that includes Formula I, wherein the composition isadministered to the subject in a dose of about 333 mg at a frequency ofat least one member selected from the group consisting of two times aday and three times a day.

In still another embodiment, the invention is a method of treating ahuman having an autism spectrum disorder, comprising the step ofadministering to the human a composition that includes Formula I,wherein the composition is administered to the subject in a dose ofabout 333 mg at a frequency of at least one member selected from thegroup consisting of two times a day and three times a day.

In still another embodiment, the invention is a method of treating ahuman having an autism spectrum disorder, comprising the step ofadministering to the human a composition that includes Formula I,wherein the composition is administered to the subject in a dose of atleast about 333 mg at a frequency of at least one member selected fromthe group consisting of one time a day, two times a day and three timesa day.

In still another embodiment, the invention is a method of treating ahuman having an autism spectrum disorder, comprising the step ofadministering to the human a composition that includes Formula I,wherein the composition is administered to the subject in a dose that istherapeutically effective.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Table 1.

DESCRIPTION

For the purposes of promoting an understanding of the principles of thenovel technology, reference will now be made to the preferredembodiments thereof, and specific language will be used to describe thesame. It will nevertheless be understood that no limitation of the scopeof the novel technology is thereby intended, such alterations,modifications, and further applications of the principles of the noveltechnology being contemplated as would normally occur to one skilled inthe art to which the novel technology relates.

In an embodiment, the invention is a method of treating a subject havingan autism spectrum disorder, comprising the step of administering to thesubject a composition that includes at least one homotaurine analog thatdecreases neuronal glutamatergic signaling.

In another embodiment, the invention is a method of treating a subjecthaving an autism spectrum disorder, comprising the step of administeringto the subject a composition that includes at least one homotaurineanalog. The homotaurine analog employed in the methods of the inventionare homotaurine analogs that can decrease neuronal glutamatergicsignaling.

Autism spectrum disorder is a developmental disorder that affects anindividual's ability to communicate, form relationships with others andrespond appropriately to the environment. Some individuals with autismspectrum disorder are high functioning, with speech and intelligencewithin normal range. Other individuals with autism spectrum disorder maybe nonverbal and/or have varying degrees of mental retardation. Autismspectrum disorder can include Asperger's syndrome (also referred to as“Asperger's disorder”), idiopathic autism (e.g., autism of unknownorigin) and Pervasive Developmental Disorder Not Otherwise Specified(PDD-NOS). One of skill in the art would be able to diagnosis anindividual with autism spectrum disorder and determine whether theindividual has idiopathic autism, PDD-NOS or Asperger's syndrome,employing well-known clinical criteria as described, for example, inDiagnostic and Statistical Manual of Mental Disorders (DSMMD) (4th ed.,pp. 70-71) Washington, D.C., American Psychiatric, 1994. Exemplarydiagnostic criteria listed in the DSMMD include:

Autistic Disorder

An autism screening tool must meet all three primary areas defined bythe DSM-IV description for autistic disorder (#'s 1-3 under A below) toqualify for a positive rating from First Signs:

A. A total of six (or more) items from (1), (2), and (3), with at leasttwo from (1), and one each from (2) and (3):

(1) qualitative impairment in social interaction, as manifested by atleast two of the following:

(a) marked impairment in the use of multiple nonverbal behaviors, suchas eye-to-eye gaze, facial expression, body postures, and gestures toregulate social interaction

(b) failure to develop peer relationships appropriate to developmentallevel

(c) a lack of spontaneous seeking to share enjoyment, interests, orachievements with other people (e.g., by a lack of showing, bringing, orpointing out objects of interest)

(d) lack of social or emotional reciprocity

(2) qualitative impairments in communication, as manifested by at leastone of the following:

(a) delay in, or total lack of, the development of spoken language (notaccompanied by an attempt to compensate through alternative modes ofcommunication such as gesture or mime)

(b) in individuals with adequate speech, marked impairment in theability to initiate or sustain a conversation with others

(c) stereotyped and repetitive use of language or idiosyncratic language

(d) lack of varied, spontaneous make-believe play or social imitativeplay appropriate to developmental level

(3) restricted, repetitive, and stereotyped patterns of behavior,interests, and activities as manifested by at least one of thefollowing:

(a) encompassing preoccupation with one or more stereotyped andrestricted patterns of interest that is abnormal either in intensity orfocus

(b) apparently inflexible adherence to specific, nonfunctional routinesor rituals

(c) stereotyped and repetitive motor mannerisms (e.g., hand or fingerflapping or twisting or complex whole-body movements)

(d) persistent preoccupation with parts of objects

B. Delays or abnormal functioning in at least one of the followingareas, with onset prior to age 3 years: (1) social interaction, (2)language as used in social communication, or (3) symbolic or imaginativeplay.

C. The disturbance is not better accounted for by Rett's disorder orchildhood disintegrative disorder.

Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS)

Pervasive Developmental Disorder, Not Otherwise Specified (PDD-NOS) is adiagnosis often considered for children who show some signs of autismspectrum disorder, but who do not meet the specific diagnostic criteriafor other Pervasive Developmental Disorders (PDDs) (see, for example,Diagnostic and Statistical Manual of Mental Disorders (4th ed., pp.70-71) Washington, D.C., American Psychiatric, 1994). Deficits in peerrelations and unusual sensitivities are generally observed inindividuals with PDD-NOS, whereas social skills are generally lessimpaired than in idiopathic autism.

This category should be used when there is a severe and pervasiveimpairment in the development of reciprocal social interaction or verbaland nonverbal communication skills, or when stereotyped behavior,interests, and activities are present, but the criteria are not met fora specific pervasive developmental disorder, schizophrenia, schizotypalpersonality disorder, or avoidant personality disorder. For example,this category includes “atypical autism”—presentations that do not meetthe criteria for autistic disorder because of late age of onset,atypical symptomatology, or subthreshold symptomatology, or all or anycombination thereof.

Asperger's Disorder (also referred to herein as “Asperger Syndrome”)

In contrast to individuals with idiopathic autism (autism with unknownorigin) individuals with Asperger's syndrome generally do not manifest adelay in spoken language development (see, for example, Diagnostic andStatistical Manual of Mental Disorders (4th ed., pp. 70-71) Washington,D.C., American Psychiatric, 1994). However, they can have seriousdeficits in social and communication skills; and often have obsessive,repetitive routines and preoccupations with a particular subject matter.Idiosyncratic interests are common and may take the form of an unusualand/or highly circumscribed interest (e.g., in train schedules, theweather).

An Asperger/HFA screening tool must meet all six areas defined by theDSM-IV description of Asperger Syndrome (A-F below) to qualify for apositive rating from First Signs:

A. Qualitative impairment in social interaction, as manifested by atleast two of the following:

(1) marked impairment in the use of multiple nonverbal behaviors, suchas eye-to-eye gaze, facial expression, body postures, and gestures toregulate social interaction

(2) failure to develop peer relationships appropriate to developmentallevel

(3) a lack of spontaneous seeking to share enjoyment, interests, orachievements with other people (e.g., by a lack of showing, bringing, orpointing out objects of interest to other people)

(4) lack of social or emotional reciprocity

B. Restricted, repetitive, and stereotyped patterns of behavior,interests, and activities, as manifested by at least one of thefollowing:

(1) encompassing preoccupation with one or more stereotyped andrestricted patterns of interest that is abnormal either in intensity orfocus

(2) apparently inflexible adherence to specific, nonfunctional routinesor rituals

(3) stereotyped and repetitive motor mannerisms (e.g., hand or fingerflapping or twisting, or complex whole-body movements)

(4) persistent preoccupation with parts of objects

C. The disturbance causes clinically significant impairment in social,occupational, or other important areas of functioning.

D. There is no clinically significant general delay in language (e.g.,single words used by age 2 years, communicative phrases used by age 3years).

E. There is no clinically significant delay in cognitive development orin the development of age-appropriate self-help skills, adaptivebehavior (other than in social interaction), and curiosity about theenvironment in childhood.

F. Criteria are not met for another specific pervasive developmentaldisorder or schizophrenia.

“Homotaurine analog,” as used herein, means a compound that has astructure that is similar to taurine but differs by at least oneelement. For example, taltrimide (Formula II), calcium acamprosate(Formula I) and tauromustine (Formula III) are homotaurine analogs(Gupta, R. C., et al., Curr. Medicinal Chem. 12:2021-2039 (2005)).

The methods of the invention employ homotaurine analogs (See, forexample, U.S. Pat. Nos. 6,391,922 and 5,602,150, each of which isincorporated herein in its entirety; U.S. Patent Application Nos.:2002/0013366, 2002/0119912, 2004/0102525, each of which is incorporatedherein in its entirety; Harris, B. R., et al., Alcohol Clin Exp Res 26:1779-1793 (2002); and Pierrefiche, O., et al., Neuropharmacology47:35-45 (2004)).

The methods of the invention employ the homotaurine analog of Formula I:

The chemical name of Formula I is calcium acetylaminopropane sulfonate,calcium bis-acetyl homotaurine or calcium N-acetylhomotaurine. Thechemical formula for Formula I is C10H20N2O8S2Ca. Formula I is referredto as CAMPRAL® (acamprosate calcium, also referred to herein as “calciumacamprosate”). Formula I decreases neuronal glutamateric signaling.

“Decreases neuronal glutamatergic signaling,” as used herein, means thatthe homotaurine analog reduces the amount of effect of glutamate onpostsynaptic transmission in neurons. A decrease in neuronalglutamatergic signaling can be, for example, consequent to a decrease inrelease of glutamate from neurons and/or limiting or diminishing theability of synaptic glutamate to mediate cell signaling in neurons.Techniques to assess whether a homotaurine analog can decrease neuronalglutamateric signaling are well established and known to one of skill inthe art and include, for example, the use of paired pulse facilitationto measure glutamate release using electrophysiologic measure, asdescribed, for example, by MacIver, M., et al., Laboratory Investigation85 (Issue 4), pp 823-834 (1996).

The autism spectrum disorder treated by the methods of the invention caninclude at least one member selected from the group consisting ofAsperger's syndrome, an idiopathic autism and a pervasive developmentaldisorder not otherwise specified (PDD-NOS).

In an embodiment, the subject that has autism spectrum disorder also hasfragile X syndrome.

The homotaurine analog employed in the methods of the invention to treatan autism spectrum disorder (Asperger's syndrome, idiopathic autism,PDD-NOS) and/or fragile X syndrome can include at least one memberselected from the group consisting of an acetylaminopropane sulfonateand an acetylaminopropane sulfonate salt. In a particular embodiment,the acetylaminopropane sulfonate salt can include a calciumacetylaminopropane sulfonate represented by Formula I:

The homotaurine analog employed in some of the methods of the invention(e.g., calcium acetylaminopropane sulfonate, Formula I) can beadministered to the subject at a dose of at least one member selectedfrom the group consisting of about a 333 mg dose, about a 666 mg dose,about a 999 mg dose, about a 1332 mg dose, about a 1665 mg dose, about a1998 mg dose, about a 2331 mg dose, about a 2664 mg dose and about a2997 mg dose. The homotaurine analog (e.g., Formula I) employed in themethods of the invention can be administered to the subject in a dose ofabout 1221 mg/day or in a dose of between about 333 mg/day to about 1999mg/day. In an embodiment, the subject is administered a dose of thehomotaurine analog (e.g., Formula I) of about a 333 mg dose. In anotherembodiment, the subject is administered a dose of the homotaurine analog(e.g., Formula I) of about a 666 mg dose.

The homotaurine analogs (e.g., Formula I) can be administered to thesubject (e.g., a human subject) daily in a single dose or in multipledoses (e.g., two doses, three doses, four doses, five doses, six doses,seven doses, eight doses, nine doses, ten doses) a day. The dosage andfrequency of dosing of the subject can within the knowledge of one ofskill in the art based on age, other medications and tolerance of thehomotaurine analog.

In another embodiment, the invention is a method of treating a subjecthaving fragile X syndrome, comprising the step of administering to thesubject a composition that includes at least one homotaurine analog. Thehomotaurine analog employed to treat the subject having fragile xsyndrome, autism or a combination of autism and fragile X syndrome candecrease neuronal glutamatergic signaling. The subject having fragile Xsyndrome treated by the methods of the invention can also further havean autism spectrum disorder.

In yet another embodiment, the invention is a method of treating a humanhaving fragile X syndrome, comprising the step of administering to thehuman a composition that includes Formula I, wherein the composition isadministered to the subject in a dose of about 333 mg at a frequency ofat least one member selected from the group consisting of two times aday and three times a day. The human treated with Formula I that hasfragile X syndrome can further have an autism spectrum disorder.

In still another embodiment, the invention is a method of treating ahuman having an autism spectrum disorder, comprising the step ofadministering to the human a composition that includes Formula I,wherein the composition is administered to the subject in a dose ofabout 333 mg at a frequency of at least one member selected from thegroup consisting of two times a day and three times a day. The humanthat has autism spectrum disorder that is treated by administeringFormula I can further have fragile X syndrome.

“Therapeutically effective amount,” as used herein, means an amount of ahomotaurine analog that diminishes or ameliorates symptoms of at leastone condition selected from the group consisting of an autism spectrumdisorder and fragile X syndrome. One of skill in the art would be ableto determine the therapeutically effective amount of a homotaurineanalog for use in the methods described herein.

The methods of the invention can further include the step ofadministering compositions to the subject that treat irritability,anxiety, inattention and hyperactivity in the subjects, as needed(referred to as “additional treatment”). The additional treatment couldbe administered before or after administration of the homotaurine analogto the subject. Suitable compositions for administration to the subjectin addition to the homotaurine analog can include, for example,aripiprazole and risperidone in subject having autism; selectiveserotonin reuptake inhibitors (SSRIs) to treat anxiety and stimulants totreat ADHD-like symptoms in subjects with fragile X syndrome;stimulants, alpha 2-agonists and atomoxetine to manage ADHD-likesymptoms and SSRIs; and mirtazapine for anxiety in subjects withidiopathic autism. One of skill in the art would be able to identifysubjects who need additional treatment and the additional treatment thatis required.

FXS represents the most common known cause of autism and relateddisorders. Approximately 1 in 4 (25%) to 1 in 3 (33%) individuals withFXS additionally meet criteria for autistic disorder (King, State et al.1997; Bailey, Hatton et al. 2001; Rogers, Wehner et al. 2001). About 2in 3 (67%) males with FXS are thought to exhibit behavior consistentwith the broader autism phenotype (Clifford, Dissanayake et al. 2007).

Experiments utilizing cellular and animal modeling, in recent years havecontributed to our understanding of the possible etiology of FXS. Someof this work has reported that excessive metabotropic glutamate receptoractivation (specifically mGluR5 activation) may be involved in thepathogenesis of FXS (Bear, Huber et al. 2004; Bear 2005; Dolen and Bear2005; Dolen, Osterweil et al. 2007; Bear, Dolen et al. 2008; Dolen andBear 2008). In some experiments, the mGluR5 antagonist MPEP(2-methyl-6-phenylethynl)-pyridine) has demonstrated its apparentability to reverse aspects of the FXS phenotype in animal models for thesyndrome (McBride, Choi et al. 2005; Yan, Rammal et al. 2005; Tucker,Richards et al. 2006; Dolen, Osterweil et al. 2007).

Fragile X syndrome (FXS) is the most common inherited form ofintellectual disability. FXS is the result of an unstablecysteine-guanine-guanine (CGG) trinucleotide repeat expansion (>200repeats) within the fragile X mental retardation 1 gene (FMR1) promoterregion located near the long arm of the X chromosome (Pieretti, Zhang etal. 1991). This expansion leads to transcriptional silencing of the FMR1gene and the absence of fragile X mental retardation protein (FMRP)(Devys, Lutz et al. 1993). Due to the location of the FMR1 gene on the Xchromosome, females with the full mutation are, in general, more mildlyaffected than males secondary to potential FMRP production from thenon-mutated FMR1 allele. The full mutation gene frequency is about1/2500 (Hagerman 2008).

FMRP is an RNA binding protein important to dendritic maturity andsynaptic plasticity (Greenough, Klintsova et al. 2001). This importantrole in cortical development is likely in part due to the action of FMRPas an end product inhibitor of group 1 metabotropic glutamate receptor(mGluR1 and mGluR5) mediated dendritic RNA translation (Bear, Huber etal. 2004; Ronesi and Huber 2008). The impact of excess mGluR activationdue to loss of inhibitory FMRP control can be seen in the FMR1 knockoutmouse model. In this model, excess hippocampal and cerebellar long termdepression (LTD), excess AMPA receptor internalization, abnormaldendritic morphology, and reduced seizure threshold are all consistentwith excessive group 1 mGluR activation (Bear, Huber et al. 2004).

Some of the treatment implications of excessive mGluR activation havebeen studied. In the mouse model, mGluR down regulation by treatmentwith MPEP (2-methyl-6-(phenylethynyl)-pyridine) and other mGluR5antagonists has been shown to reverse phenotypic characteristics,including audiogenic seizures, altered prepulse inhibition (PPI), andopen field hyperactivity (Chuang, Zhao et al. 2005; Yan, Rammal et al.2005; de Vrij, Levenga et al. 2008). MPEP has rescued aberrant courtshipbehavior in the Drosophila model of FXS (McBride, Choi et al. 2005).Genetic down regulation of mGluR5 executed by crossing a FMR1 knockoutmouse with a mGluR5 heterozygous knockout resulted in reversal ofseveral FMR1 knockout characteristics, including dendritic spine changesand excess protein synthesis (Dolen and Bear 2008).

Berry-Kravis and colleagues (2008) conducted a pilot single dose trialof the mGluR5 antagonist fenobam (50-150 mg) focused on tolerability andpharmacokinetic assessment in twelve adults (6 males, 6 females; meanage, 23.9+/−5.4 years) with full mutation FXS (Berry-Kravis, Hessl etal. 2009). Fenobam was generally well tolerated with only 3 (25%)subjects exhibiting mild sedation. Wide inter-subject pharmacokineticvariability was noted. Six (50%) subjects showed at least a 20%improvement in PPI one hour post fenobam dosing. The authors reportedthat nine (75%) subjects experienced clinical benefit, including reducedhyperactivity and anxiety that was not dose dependent and did notcompletely correlate with PPI response.

Acamprosate, calcium acetylhomotaurine, also known as3-acetamidopropane-1-sulfonic acid, is approved by the United StatesFood and Drug Administration to administer to patients for themaintenance of abstinence from alcohol in patients with alcoholdependence. See for example, International Publication Number WO02/102388 A3, incorporated by reference herein in its entirety.

Recent research into the mechanism of action of acamprosate has focusedon mGluR5 antagonism (Harris, Prendergast et al. 2002; Blednov and AdronHarris 2008; Gupta, Syed et al. 2008). In rat brain specimens, Harris etal. (2002) initially demonstrated that acamprosate had binding andfunctional characteristics consistent with an mGluR antagonist combinedwith functional similarity to the non-competitive mGluR5 antagonistSIB-1893 (Harris, Prendergast et al. 2002). Acamprosate and MPEP haveboth been associated with increased sedative effects of alcohol andreduced alcohol withdrawal in mice; no effects of acamprosate or MPEPwere noted in mGluR5 knockout mice (Blednov and Adron Harris 2008).Gupta and colleagues (2008) demonstrated that acamprosate and MPEP bothdose dependently reduced ethanol drinking in the drinking-in-the-darkmouse model (Gupta, Syed et al. 2008). In a conflicting report, atconcentrations typically achieved in humans, acamprosate did notmodulate the function of many neuroreceptors, including mGluR receptors,in an electrophysiological study in Xenopus oocytes (Reilly, Lobo et al.2008). Additional preclinical data has pointed to potential weak NMDAreceptor antagonism, GABA(A) receptor agonism, and anti-oxidant effectsas potentially contributing to the effect of the drug in early alcoholabstinence (Mann, Kiefer et al. 2008).

In this report, no effects of acamprosate or MPEP were noted in mGluR5knockout mice (Blednov and Adron Harris 2008). Also recently, Gupta etal. (2008) demonstrated that both acamprosate and MPEP dose dependentlyreduced ethanol drinking in the drinking-in-the-dark mouse model (Gupta,Syed et al. 2008). And MPEP, itself, has been shown to possibly reversesome aspects of the FXS phenotype in several animal models for thecondition.

According to current FDA guidelines acamprosate can be administered tohuman patients at a dosing level of about 1,998 mg/kg/day which is theU.S. FDA approved dosing of acamprosate used to treat alcohol dependencein adults. The calcium salt of the compound is commercially availableand sold in tablets that include about 333 mg of the active ingredientper tablet. Tablets that have an enteric coating are also available toadminister to patents that are able to swallow tablets.

In some embodiments patients already being treated with psychotropicdrug use will be allowed to continue to use these drugs throughout thestudy as long as the dose of psychotropic drugs remains the same duringthe trial. Experimental primary outcome measures in the studies reportedon herein and any ongoing studies and clinical assessments may includetests such as the Clinical Global Impression Improvement (CGI-I) scale(Guy 1976) and the Aberrant Behavior Checklist (ABC) (Aman, Singh et al.1985). The ABC is made up of subscales of behaviors including SocialWithdrawal, Irritability, Stereotypy, Hyperactivity, and InappropriateSpeech. The ABC is commonly used in drug trials involving persons withdevelopmental disability and the composite score on the measure hasshown good reliability as an outcome measure specifically in personswith FXS (Berry-Kravis, Krause et al. 2006). Treatment responses usingthese tests are determined by scoring the behaviors of the patients' aCGI-I score of “much improved” or “very much improved” and a 25% orgreater improvement in the ABC composite score. The tolerability ofacamprosate can be readily assessed throughout the course of treatmentwith the drug via the use of standard side-effect profile checklists atall study visits and by the following baseline and study completionmeasures: physical examination; laboratory studies including completeblood count, comprehensive metabolic panel, and lipid panel;electrocardiograms.

EXPERIMENTAL

1. Treatment of Young Adult Males Presenting with Full Mutation FXS.

This study sample included 4 young adult males (mean age, 20.3 years;range, 18-23 years) with full mutation FXS. The parents of each patientgave their written, informed consent for treatment within our clinic.All patients had a comorbid clinical diagnosis of autistic disorder(autism) utilizing Diagnostic and Statistical Manual of MentalDisorders, 4^(th) Edition, Text Revision criteria (American PsychiatricAssociation 2000). Patients A and B had this diagnosis corroborated bythe Autism Diagnostic Interview-Revised (ADI-R) (Lord, Rutter et al.1994). At baseline, each patient had linguistic communication. Twopatients (A, B) receiving concomitant psychotropic drugs were continuedat the same doses during the trial (see Table 1).

Acamprosate was initiated at 666 mg every morning and increased in 666mg increments every 2 weeks as tolerated to a maximum dose of 666 mgthree times daily (recommended dose for treatment of alcohol-dependentadults) (Forest Pharmaceuticals 2005). Prior to reaching a maintenancedose, and in between monthly clinic visits, phone calls were made everytwo weeks to the primary caregiver to assess for treatment response anddrug tolerability. Global improvement, as measured by the ClinicalGlobal Impressions-Improvement (Guy 1976) (CGI-I) scale was assigned atthe time of last follow-up visit. The CGI-I scale is rated from 1-7(1=very much improved; 2=much improved; 3=minimally improved; 4=nochange; 5=minimally worse; 6=much worse; 7=very much worse). The CGI-Iratings described change in target symptoms defined at the baselinevisit (see Table 1). Patients were considered treatment responders ifassigned a CGI-I score of 1 or 2 at the final follow-up visit. Thisstudy was approved by our local Institutional Review Board and, thus,has been performed in accordance with the ethical standards laid down inthe 1964 Declaration of Helsinki.

Results

Case 1

A is a 20-year-old Caucasian male with mild intellectual disability. Inaddition to the characteristic features of autism (social impairment,communication impairment, repetitive phenomena), A had a history ofsignificant physical aggression, anxiety, inattention, andhyperactivity. Previous trials of aripiprazole and risperidone wereunsuccessful in limiting A's aggression. In addition to his currentmedication regimen, including propranolol, dextroamphetamine, andziprasidone, a trial of acamprosate targeting aggression and social andcommunication impairments was initiated. Acamprosate was started at 666mg every morning and increased to a target dose of 666 mg three timesdaily over 4 weeks. During the 44-week treatment, A exhibited increasedcommunicative use of language marked by an expanded expressivevocabulary, increased grammatical complexity of speech, and improvedpragmatic skills. For example, within 2 weeks of reaching his maximumdose, A reportedly started to appropriately initiate conversation withneighbors as they walked by his home while he was sitting on his frontporch. A's increased mean length of utterance when responding toquestions was clear at each follow-up visit. Additionally, A exhibiteddecreased physical aggression, use of foul language, and defiance duringthe acamprosate trial. He was deemed to be “very much improved” asdetermined by a CGI-I score of 1. No adverse effects were observed orreported.

Case 2

B is an 18-year-old Caucasian male with moderate intellectualdisability. B had a history of intermittent physical aggression that wasreduced significantly with aripiprazole. A trial of acamprosatetargeting social skill deficits and communication impairment was begun.At baseline, B exhibited significantly impaired language pragmatics,grammatical complexity of speech, and expressive vocabulary. He wouldrarely use single words in social settings and only on occasion utilizedshort sentences with close family members at home Acamprosate wasstarted at 666 mg every morning and increased to a target dose of 666 mgthree times daily over 4 weeks. B experienced nausea and intermittentemesis requiring a dose reduction to 666 mg twice daily. During 40 weeksof acamprosate treatment, he utilized coherent full sentences in socialsettings for the first time, surprising family friends and peers. Duringfollow-up visits, B's increased grammatical complexity of speech,expressive vocabulary, and pragmatic use of language were all evident.He was deemed to be “very much improved” as determined by a CGI-I scoreof 1.

Case 3

C is a 23-year-old Caucasian male with moderate intellectual disability.H is primary target symptoms were core symptoms of autism, includingsocial skill deficits and repetitive behavior marked by repetitivequestioning. C was unable to tolerate initial dosing of acamprosatemonotherapy started at 666 mg every morning due to sedation and emesis.With a dose reduction to 333 mg daily, the sedation and emesis remittedand he continued the drug for 24 weeks. C's language pragmatics wasdescribed as improved, marked by an increased ability to convey hisneeds and interests in socially appropriate ways. He was described asasking more appropriate and not just repetitive questions, and generally“talking more on topic”. He was deemed “much improved” as determined bya CGI-I score of 2.

Case 4

D is an 18-year-old Caucasian male with mild intellectual disability.His primary target symptoms were irritability and core symptoms ofPDD-NOS including deficits of social communication. D was dosed up to666 mg three times daily, but developed gastrointestinal upset on threetimes daily dosing. A dosing change to 999 mg twice daily was welltolerated for the duration of a total of 28 weeks of acamprosatetreatment. D remained on stable concomitant dosing of aripiprazole,clonidine, and fluoxetine during treatment with acamprosate. Duringacamprosate treatment, D was described as exhibiting more appropriateuse of sentences including use of an expanded vocabulary. D wasgenerally more talkative during treatment. D exhibited reduced irritablebehavior throughout acamprosate treatment. He was deemed “much improved”as determined by a CGI-I score of 2.

The mean final dose of acamprosate for the four young adult male FXSparticipants was 1415 mg/day (range, 333-1998 mg/day). Patients receivedthe drug for a minimum of 24 weeks (mean duration, 34 weeks; range,24-44 weeks). All 4 patients were deemed responders. Each subjectexhibited positive expressive language change, including elements ofimproved pragmatics, grammatical complexity, and vocabulary. Thisincreased linguistic communication was not associated with a reductionin gaze aversion or other forms of impaired non-verbal communication.One subject experienced sedation and two experienced nausea and/oremesis which appeared to be dose related.

2. Treatment of Juvenile Diagnosed with Full Mutation FXS.

In this study, acamprosate was initiated at 333 mg every morning andincreased in 333 mg increments every 2 weeks as tolerated to a maximumdose of 666 mg three times daily (recommended dose for treatment ofalcohol-dependent adults) (Forest Pharmaceuticals 2005). Prior toreaching a maintenance dose, and in between monthly clinic visits, phonecalls were made every two weeks to the primary caregiver to assess fortreatment response and drug tolerability. Drug dosing was held at aconsistent level unless the patient exhibited untolerable side-effectsfrom the therapy. Global improvement, as measured by the Clinical GlobalImpressions-Improvement (Guy 1976) (CGI-I) scale was assigned at thetime of last follow-up visit. The CGI-I scale is rated from 1-7 (1=verymuch improved; 2=much improved; 3=minimally improved; 4=no change;5=minimally worse; 6=much worse; 7=very much worse). The CGI-I ratingsdescribed change in target symptoms defined at the baseline visit (seeTable 1). Patients were considered treatment responders if assigned aCGI-I score of 1 or 2 at the final follow-up visit.

Case 5

E is a 9-year-old Caucasian male with mild intellectual disability andfull mutation FXS. His primary target symptoms include social use oflanguage, inattention, hyperactivity, and general social relatedness. Ehas a comorbid diagnosis of PDD-NOS. E remained on a stable dose ofconcomitant aripiprazole throughout treatment with acamprosate. E wasmaintained on a starting dose of acamprosate at 333 mg every morning dueto sufficient treatment response at this dose over 6 weeks of treatment.During treatment, E was described by his mother as seeming like “hisbrain has come back.” E exhibited improved language pragmatics, improvedfocus, and remained calmer during use of acamprosate. He was deemed“very much improved” as determined by a CGI-I score of 1.

3. Treatment of Juveniles Diagnosed with Idiopathic Autism.

In this study, acamprosate was initiated at 333 mg every morning andincreased in 333 mg increments every 2 weeks as tolerated to a maximumdose of 666 mg three times daily (recommended dose for treatment ofalcohol-dependent adults) (Forest Pharmaceuticals 2005). Prior toreaching a maintenance dose, and in between monthly clinic visits, phonecalls were made every two weeks to the primary caregiver to assess fortreatment response and drug tolerability. Drug dosing was held at aconsistent level unless the patient protested untolerable side-effectsdue to the therapy. Global improvement, as measured by the ClinicalGlobal Impressions-Improvement (Guy 1976) (CGI-I) scale was assigned atthe time of last follow-up visit. The CGI-I scale is rated from 1-7(1=very much improved; 2=much improved; 3=minimally improved; 4=nochange; 5=minimally worse; 6=much worse; 7=very much worse). The CGI-Iratings described change in target symptoms defined at the baselinevisit (see Table 1). Patients were considered treatment responders ifassigned a CGI-I score of 1 or 2 at the final follow-up visit. Thisstudy was approved by our local Institutional Review Board and, thus,has been performed in accordance with the ethical standards laid down inthe 1964 Declaration of Helsinki.

Case 6

F is a 10-year-old male with idiopathic autistic disorder and mildintellectual disability. His primary target symptoms of treatment weresocial responsiveness and use of language. He received acamprosatetreatment for 14 weeks with a final dosing of 666 mg in the morning, 333mg midday, and 333 mg in the evening. F suffered from loose stoolsduring acamprosate treatment. For F acamprosate treatment was associatedwith improved social responses, increased verbalizations, and improvedeye contact. He was deemed “much improved” as determined by a CGI-Iscore of 2.

Case 7

G is a 13-year-old male with idiopathic autistic disorder and moderateintellectual disability. His primary target symptoms of treatment weresocial responsiveness and inattention. He received acamprosate treatmentfor 10 weeks with a final dosing of 333 mg twice daily. G remained onstable dosing of concomitant atomoxetine treatment throughout hisacamprosate trial. For G acamprosate treatment was associated withimproved attention and mildly improved social behavior. He was deemed“minimally improved” as determined by a CGI-I score of 3.

Case 8

H is a 12-year-old female with idiopathic autistic disorder and moderateintellectual disability. Her primary target symptoms of treatment weresocial responsiveness and use of language. She received acamprosatetreatment for 28 weeks with a final dosing of 333 mg three times daily.She remained on stable dosing of concomitant risperidone and clonidinethroughout her treatment with acamprosate. For H acamprosate treatmentwas associated with increased use of single words, generally improvedsocial communication, and improved eye contact. She was deemed “verymuch improved” as determined by a CGI-I score of 1.

Case 9

I is an 11-year-old male with idiopathic autistic disorder and moderateintellectual disability. His primary target symptoms of treatment weresocial responsiveness and use of language. He received acamprosatetreatment for 20 weeks with a final dosing of 333 mg three times daily.I remained on stable dosing of concomitant sertraline during hisacamprosate trial. For I, acamprosate treatment was associated withinitial improvement in social behavior that waned after 8-12 weeks oftreatment. I additionally suffered from reduced appetite andgastrointestinal distress during treatment. He was described as “nochange” as determined by a CGI-I score of 4.

Case 10

J is a 6-year-old male with idiopathic autistic disorder and severeintellectual disability. His primary target symptoms of treatment weresocial responsiveness, inattention, and use of language. He receivedacamprosate treatment for 20 weeks with a final dosing of 333 mg threetimes daily. For J acamprosate treatment was associated with improvedfollowing of directions, improved focus, and increased use ofcommunication with gestures. J suffered from reduced appetite duringacamprosate treatment. He was deemed “much improved” as determined by aCGI-I score of 2.

Case 11

K is an 8-year-old male with idiopathic autistic disorder and moderateintellectual disability. His primary target symptoms of treatment weresocial responsiveness, inattention, and use of language. He receivedacamprosate treatment for 30 weeks with a final dosing of 666 mg in themorning, 333 mg midday, and 333 mg in the evening. K suffered fromreduced appetite and gastrointestinal distress that waned after severalweeks of treatment with acamprosate. For K acamprosate treatment wasassociated with increased meaningful use of words, improved socialrelatedness, and improved focus. He was deemed “much improved” asdetermined by a CGI-I score of 2.

The six juveniles (mean age 10.3 years; range 6-13 years) withidiopathic autism were treated with a mean acamprosate dose of 999mg/day over a mean 20.33 weeks of treatment.

All but one of the 11 patients treated with acamprosate calcium in thisstudy showed a measurable improvement in standard assessments offunctionality. Overall, use of acamprosate was associated with increaseduse of communicative language in all subjects. In all cases pragmaticlanguage change was noted, as linguistic communication was more socialin nature and the content more appropriate to the context of a givendiscussion. Despite improved pragmatics, nonverbal aspects of socialcommunication including eye gaze, did not appear to changesignificantly. Acamprosate may enhance standard measures of expressivelanguage, including assessment of mean length of utterance, vocabulary,and pragmatics of speech, along with systematic measures of interferingbehaviors such as aggression.

The majority of both adult and juvenile human patients diagnosed with aform of autism spectrum disorder, show measurable improvement whentreated with acamprosate. These clinical studies show that acamprosatecan improve, for example, social behavior and use of language, resultingin a remarkable treatment for core symptoms of autism and/or fragile Xsyndrome, including communication and social impairments in theseindividuals. In addition to these remarkable and unexpected resultsstill other advantages of using acamprosate to treat autism spectrumdisorders include the commercial availability of the drug, limiteddrug-drug interactions given lack of hepatic metabolism, anddemonstrated pharmacokinetic and safety profiles in human adults.

Additional potential properties of acamprosate, including mild NMDAreceptor antagonism and GABA(A) agonism, could also be responsible forthe treatment response noted. The possible contribution of thesenon-mGluR5 mediated treatment effects is supported by a report of modesttreatment effects with use of the uncompetitive NMDA receptor antagonistmemantine in an open-label study in 6 persons with FXS and a comorbidautism spectrum disorder (Erickson, Mullett et al. 2009).

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While the novel technology has been illustrated and described in detailin the figures and foregoing description, the same is to be consideredas illustrative and not restrictive in character, it being understoodthat only the preferred embodiments have been shown and described andthat al changes and modifications that come within the spirit of thenovel technology are desired to be protected. As well, while the noveltechnology was illustrated using specific examples, theoreticalarguments, accounts, and illustrations, these illustrations and theaccompanying discussion should by no means be interpreted as limitingthe technology. All patents, patent applications, and references totexts, scientific treatises, publications, and the like referenced inthis application are incorporated herein by reference in their entirety.

What is claimed is:
 1. A method of treating a subject having an autismspectrum disorder, comprising the step of administering to the subject acomposition that includes at least one homotaurine analog, wherein thehomotaurine analog is at least one member selected from the groupconsisting of an acetylaminopropane sulfonate and an acetylaminopropanesulfonate salt, wherein the homotaurine analog is administered to thesubject at a dose of at least one member selected from the groupconsisting of about a 333 mg dose, about a 666 mg dose, about a 999 mgdose, about a 1332 mg dose, about a 1665 mg dose, about a 1998 mg dose,about a 2331 mg dose, about a 2664 mg dose and about a 2997 mg dose. 2.The method of claim 1, wherein the homotaurine analog decreases neuronalglutamatergic signaling.
 3. The method of claim 1, wherein the autismspectrum disorder includes Asperger's syndrome.
 4. The method of claim1, wherein the autism spectrum disorder includes an idiopathic autism.5. The method of claim 1, wherein the autism spectrum disorder includesa pervasive developmental disorder not otherwise specified.
 6. Themethod of claim 1, wherein the subject further has fragile X syndrome.7. The method of claim 1, wherein the acetylaminopropane sulfonate saltincludes a calcium acetylaminopropane sulfonate represented by FormulaI:


8. The method of claim 1, wherein the dose is about the 333 mg dose. 9.The method of claim 1, wherein the dose is about the 666 mg dose. 10.The method of claim 1, wherein the dose is administered daily to thesubject in a single dose.
 11. The method of claim 1, wherein the dose isadministered daily to the subject in multiple doses.
 12. The method ofclaim 11, wherein the multiple doses are three doses.
 13. The method ofclaim 1, wherein the subject is a human.
 14. A method of treating asubject having fragile X syndrome, comprising the step of administeringto the subject a composition that includes at least one homotaurineanalog, wherein the homotaurine analog is at least one member selectedfrom the group consisting of an acetylaminopropane sulfonate and anacetylaminopropane sulfonate salt, wherein the homotaurine analog isadministered to the subject at a dose of at least one member selectedfrom the group consisting of about a 333 mg dose, about a 666 mg dose,about a 999 mg dose, about a 1332 mg dose, about a 1665 mg dose, about a1998 mg dose, about a 2331 mg dose, about a 2664 mg dose and about a2997 mg dose.
 15. The method of claim 14, wherein the homotaurine analogdecreases neuronal glutamatergic signaling.
 16. The method of claim 14,wherein the subject further has an autism spectrum disorder.
 17. Themethod of claim 14, wherein the acetylaminopropane sulfonate saltincludes a calcium acetylaminopropane sulfonate represented by FormulaI:


18. The method of claim 14, wherein the dose is about the 333 mg dose.19. The method of claim 14, wherein the dose is about the 666 mg dose.20. The method of claim 14, wherein the dose is administered daily tothe subject in a single dose.
 21. The method of claim 14, wherein thedose is administered daily to the subject in multiple doses.
 22. Themethod of claim 21, wherein the multiple doses are three doses.
 23. Themethod of claim 14, wherein the subject is a human.
 24. A method oftreating a human having fragile X syndrome, comprising the step ofadministering to the human a composition that includes Formula I:

wherein the composition is administered to the subject in a dose ofabout 333 mg at a frequency of at least one member selected from thegroup consisting of two times a day and three times a day.
 25. Themethod of claim 24, wherein the human further has an autism spectrumdisorder.
 26. A method of treating a human having an autism spectrumdisorder, comprising the step of administering to the human acomposition that includes Formula I:

wherein the composition is administered to the subject in a dose ofabout 333 mg at a frequency of at least one member selected from thegroup consisting of two times a day and three times a day.
 27. Themethod of claim 26, wherein the human further has fragile X syndrome.